Triazinones

Abstract

Novel s-triazine compounds are prepared as derivatives of the corresponding amidinourea and amidinothiourea compounds by reacting with an activated form of an acid amide to give substituted s-triazinones and thiones respectively, of the formula ##STR1## The s-triazinones and thiones are useful derivatives in analyzing for the corresponding amidinourea or amidino thiourea precursors and also have useful pharmacological properties which make them suitable for a variety of medicinal purposes including use as antidiarrheal agents.

We claim: 
     
       1. A compound of the formula ##STR283## wherein: X is oxygen or sulfur; R 1  is aryl, aryl lower alkyl, a 5 or 6 membered heterocycle or a lower alkyl substituted 5 or 6 membered heterocycle;   R 2  is hydrogen or lower alkyl;   and R 3  and R 4  are each independently selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, phenoxy-lower alkyl, diloweralkyl amino, aryl or aryl-lower alkyl, lower alkoxy, phenoxy, a 5 or 6 membered heterocycle or a lower alkyl substituted 5 or 6 membered heterocycle or R 3  and R 4  together with the nitrogen to which they are attached form a 3 to 7 membered heterocyclic ring, selected from the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl, trimethylenetriaminyl, ethyleneiminyl, and morpholinyl; and, wherein:     aryl means phenyl or phenyl in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo-lower alkyl, nitro, amino, lower alkylacylamino, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkyl acyloxy, cyano, halo-lower alkoxy or lower alkyl sulfonyl; and, 5 or 6 membered heterocycle means a heterocyclic substituent selected from the group consisting of pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyl, and morpholinyl;   and the non-toxic pharmaceutically acceptable salts thereof.   
     
     
       2. A compound according to claim 1 wherein X is oxygen. 
     
     
       3. A compound of the formula ##STR284## wherein X is oxygen or sulfur; R 1  is phenyl, benzyl or phenethyl; or phenyl, benzyl or phenethyl in which one or more of the phenyl hydrogens are substituted by lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl; pyridyl or pyridyl in which one or more of the hydrogens are substituted by lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl; R 2  is hydrogen or lower alkyl, and R 3  and R 4  are each independently selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenoxy-lower alkyl, di-lower alkyl-amino-lower alkyl or R 3  and R 4  together with the nitrogen to which they are attached form a 5 or 6 membered nitrogen heterocycle selected from the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl, and morpholinyl; and the pharmaceutically acceptable non-toxic salts thereof. 
     
     
       4. A compound according to claim 3 wherein X is oxygen. 
     
     
       5. A compound of the formula ##STR285## wherein X is oxygen or sulfur; R 1  is phenyl, pyridyl, phenyl in which one or more of the phenyl hydrogens is replaced by lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl, or pyridyl in which one or more of the hydrogens is replaced by lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl; R 2  is hydrogen or lower alkyl, and R 3  and R 4  are each independently selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, phenoxy lower alkyl, di-lower alkyl-amino lower alkyl or R 3  and R 4  together with the nitrogen to which they are attached form a 5 or 6 membered nitrogen heterocycle selected from the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl, and morpholinyl; and the pharmaceutically acceptable non-toxic salts thereof. 
     
     
       6. A compound according to claim 5 wherein X is oxygen. 
     
     
       7. A compound of the formula ##STR286## wherein: X is oxygen or sulfur; R 2  is hydrogen or lower alkyl;   R 3  and R 4  are each independently selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, phenoxy-lower alkyl, diloweralkylamino, aryl or aryl-lower alkyl, lower alkoxy, phenoxy and 5 or 6 membered heterocycles selected from the group consisting of pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, piperidyl and morpholinyl, or R 3  and R 4  together with the nitrogen to which they are attached form a 3 to 7 membered ring selected from the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl, trimethylenetriaminyl, ethyleneiminyl, and morpholinyl;   and R 5 , R 6 , R 7 , R 8  and R 9  are each independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl; and, wherein:     aryl means phenyl or phenyl in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo-lower alkyl, nitro, amino, lower alkylaclamino, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkyl acyloxy, cyano, halo-lower alkoxy and lower alkyl sulfonyl;   and the non-toxic pharmaceutically acceptable salts thereof.   
     
     
       8. A compound according to claim 7 wherein X is oxygen. 
     
     
       9. A compound according to claim 8 wherein each of R 6 , R 7  and R 8  is hydrogen; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       10. A compound according to claim 9 wherein R 3  is hydrogen; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       11. A compound according to claim 10 wherein each of R 5  and R 9  is halo, lower alkyl, lower alkoxy, or halo-lower alkyl; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       12. A compound according to claim 11 wherein each of R 5  and R 9  is lower alkyl; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       13. A compound of the formula ##STR287## wherein: X is oxygen or sulfur; R 2  is hydrogen or lower alkyl;   R 3  and R 4  are each independently selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl, cycloloweralkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy lower alkyl, phenoxy lower alkyl, diloweralkylamino, aryl, aryl lower alkyl, lower alkoxy, phenoxy, and 5 or 6 membered heterocycles selected from the group consisting of pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyl, and morpholinyl, or R 3  and R 4  together with the nitrogen to which they are attached form a 3 to 7 membered ring selected from the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl, trimethylenetriaminyl, ethyleneiminyl, and morpholinyl;   R 5  and R 9  are each independently hydrogen, lower alkyl, halo, halo lower alkyl, hydroxy, or lower alkoxy; R 6 , R 7  and R 8  are each hydrogen; and, wherein:     aryl means phenyl or phenyl in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo-lower alkyl, nitro, amino, lower alkylacylamino, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkylacyloxy, cyano, halo-lower alkoxy, and lower alkyl sulfonyl;   and the non-toxic pharmaceutically acceptable salts thereof.   
     
     
       14. A compound according to claim 13 wherein R 5  and R 9  are each halo; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       15. A compound according to claim 13 wherein R 3  is hydrogen; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       16. A compound according to claim 15 wherein R 2  is hydrogen and R 4  is hydrogen lower alkyl, hydroxyl or lower alkoxy; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       17. A compound according to claim 16 wherein R 5  and R 9  are each independently lower alkyl, lower alkoxy, halo or halo-lower alkyl; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       18. A compound of the formula ##STR288## wherein: R 2  is hydrogen or lower alkyl; R 3  and R 4  are each independently selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl, cycloloweralkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy lower alkyl, phenoxy lower alkyl, diloweralkylamino, aryl or aryl lower alkyl, lower alkoxy, and phenoxy, and 5 or 6 membered heterocycles selected from the group consisting of pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyl and morpholinyl, or R 3  and R 4  together with the nitrogen to which they are attached form a 3 to 7 membered ring selected from the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl, trimethylenetriaminyl, ethyleneiminyl, and morpholinyl;   R 6 , R 7  and R 8  are each independently hydrogen, lower alkyl, hydroxy or lower alkoxy;   R 5  and R 9  are each hydrogen, lower alkyl, hydroxy, lower alkoxy, halo, or halo lower alkyl; and, wherein:     aryl means phenyl or phenyl in which one or more of the phenyl hydrogens has been replaced by the same or different substituents selected from the group consisting of halo, lower alkyl, halo-lower alkyl, nitro, amino, lower alkylacylamino, hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkylacyloxy, cyano, halo-lower alkoxy, and lower alkyl sulfonyl;   and the non-toxic pharmaceutically acceptable salts thereof.   
     
     
       19. A compound according to claim 18 wherein R 5  and R 9  are each independently halo; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       20. A compound according to claim 18 wherein R 3  is hydrogen; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       21. A compound according to claim 20 wherein R 2  is hydrogen and R 4  is hydrogen, lower alkyl, hydroxyl or lower alkoxy; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       22. A compound according to claim 21 wherein R 5  and R 9  are each independently lower alkyl, lower alkoxy, halo, or halo-lower alkyl. 
     
     
       23. A compound of the formula ##STR289## and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       24. A compound according to claim 23 having the formula ##STR290## and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       25. A compound of the formula ##STR291## and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       26. 1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       27. 1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one hydrochloride. 
     
     
       28. 1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one; and the non-toxic pharmaceutically acceptable salts thereof. 
     
     
       29. 1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one hydrochloride.